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Imidazoline modified amino acid, and its synthesizing method and use for polypeptide marking

A technology for synthesizing polypeptides and imidazolines, applied in the chemical field, can solve problems such as product complexity and limitations, and achieve good biocompatibility, good chemical stability, completely consistent physical and chemical properties and biological activities

Inactive Publication Date: 2007-06-13
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Randomly labeled products are complex when proteins and peptides have basic or acidic side chains (which is almost unavoidable)
The present inventors have disclosed a new class of nitronyl nitrogen in previous studies. These new nitronyl nitrogens are chemically stable enough to position ESR markers for proteins and polypeptides, but these nitronyl nitrogens for positioning markers can only be linked to N-termini of proteins and peptides
Therefore, the current protein and peptide ESR labeling technology obviously limits the biological and pharmaceutical research, and the development of protein and peptide ESR fixed-point labeling technology has clear scientific significance and application value

Method used

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  • Imidazoline modified amino acid, and its synthesizing method and use for polypeptide marking
  • Imidazoline modified amino acid, and its synthesizing method and use for polypeptide marking
  • Imidazoline modified amino acid, and its synthesizing method and use for polypeptide marking

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 2

[0045] [Intermediate Preparation Example 2] Preparation of 2,3-dimethyl-2,3-dihydroxyaminobutane (compound 3)

[0046] From 10.0g (56.82mmol) 2,3-dimethyl-2,3-dinitropropane (2), 5.6g NH 4 Cl and 112ml ethanol solution (50% formed suspension was added 22.9g zinc powder under ice bath and stirring, lasted 3 hours. Then the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered under reduced pressure, and the filter cake was washed with 50% ethanol aqueous solution Repeated washing. Combine the washing liquid and filtrate, adjust pH2 with concentrated hydrochloric acid, and concentrate under reduced pressure to mud. The mud obtained is mixed with an appropriate amount of K 2 CO 3 Mix well to PH10, then place in a Soxhlet extractor with CHCl 3 Extract for 6 hours. The extract was concentrated under reduced pressure, and the residue was crystallized with petroleum ether to obtain 4.0 g (47.57%) of the title compound as colorless flaky cr...

preparation Embodiment 3

[0047] [Intermediate Preparation Example 3] Preparation of 1,3-dihydroxy-2-(4'-hydroxyphenyl)-4,4,5,5-tetramethylimidazolidine (compound 4)

[0048] A solution composed of 990mg (8.107mmol) p-hydroxybenzaldehyde, 1.196g (8.078mmol) 2,3-dimethyl-2,3-dihydroxyaminobutane (3) and 4.8ml methanol was stirred at room temperature for 6 hours, TLC The raw material point disappeared, and the reaction mixture was filtered under reduced pressure to obtain 1.47 g (72%) of the title compound as colorless crystals, ESI-MS (m / e)=2 36 [M] + ; Rf 0.64 (CHCl 3 / CH 3 OH, 10:1), mp: 168-169; IR (KBr, cm -1 ): 3340, 1600, 1450; NMR (CDCl 3 )δ=1.14(s, 4-CH 3 ), 4.78 (s, CH), 7.31-7.51 (m, 5-ArH), 7.71 (2-OH). Elemental Analysis: C 13 h 20 N 2 o 2 Calculated for: C, 66.07; H, 8.53; N, 11.85.

preparation Embodiment 4

[0049] [Intermediate Preparation Example 4] Preparation of 1,3-dioxo-2-(4'-hydroxyphenyl)-4,4,5,5-tetramethyl-2-imidazoline (compound 5)

[0050] Add 8.14g PbO to the solution of 1.47g (5.83mmol) 1,3-dihydroxyl-2-(4'-hydroxyphenyl)-4,4,5,5-tetramethylimidazolidine and 81ml methanol 2 (34.40 mmol). After stirring at room temperature for 0.5 hr, TLC showed that the starting point disappeared. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 2:1). The collected product-containing fractions were concentrated under reduced pressure to afford 1.06 g (73%) of the title compound as a blue solid. R f =0.54 (CHCl 3 / CH 3 OH, 20:1); mp84-85°C; ESI-MS(m / e)=233[M] + ; IR(KBr, cm -1 ): 3325, 1610, 1500, 1450, 765; elemental analysis: C 13 h 17 N 2 o 2 Calculated for: C, 66.93; H, 7.34; N, 12.01.

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Abstract

This invention discloses a series of new amino acids modified by imidazoline and its synthesis method and application for polypeptide fixed-point marking. This invention prepares a series of new amino acids that contain 2-substitution-1,3-dioxy-imidazoline through linking 2-substitution-1,3-dioxy-imidazoline to alkaline side chain or alpha- amino of L-Lys or L-Arg, or linking to acidic side chain oralpha-oxatyl of L-Asp or L-Glu. The invented amino acids that are modified by imidazoline have following characteristics. 1) It has satisfactory chemical stability, can tolerance various kinds of reaction condition in process of polypeptide synthesis, can maintain nature of free radical or removing remove being not invariable, also can carry out fixed-point ESR marking like normal L- amino acid in the process of polypeptide synthesis according to random place of polypeptide or protein where need to be inserted; 2) It has satisfactory biocompatibility. Polypeptide that is obtained by amino acid fixed-point marking in this invention is compared with polypeptide obtained by N end marking in present technique, the physico-chemical property and biological activity of them is completely coincident.

Description

technical field [0001] The invention relates to a modified amino acid, in particular to an amino acid modified with imidazoline, its synthesis method and the application of the modified amino acid in polypeptide site-specific labeling, belonging to the field of chemistry. Background technique [0002] In 1970, nitronyl nitrogen (2-substituted-1,3-dioxyimidazoline) of general formula 1 was synthesized for the first time (Edwin F. Ullman, Call L and Jeanne H. Osiecki, Stable freeradicals: New Imino, Amidino and Carbamoyl nitroxides, J. Org. Chem., 1970, 25, 3623-3631). In the 1990s, the role of NO in biological organisms was gradually recognized. Nitronyl Nitroxide has attracted widespread attention due to its specific reaction with NO and its paramagnetism. [0003] [0004] General formula 1. The structure of Nitronyl nitrogen oxide (2-substituted-1,3-dioxyimidazoline). R in the formula = alkyl, aryl, heteroaryl and the like. [0005] In 1993, the electron paramagneti...

Claims

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Application Information

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IPC IPC(8): C07K1/13C07K5/08C07K5/10C07K7/06C07D233/20A61K31/4174A61K38/06A61K38/07A61K38/08A61P17/18
Inventor 彭师奇赵明张建伟
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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